Ghosh J.C.,Wistar Institute |
Siegelin M.D.,Columbia University |
Vaira V.,CNR Institute of Molecular Genetics |
Tavecchio M.,Wistar Institute |
And 12 more authors.
Journal of the National Cancer Institute | Year: 2015
Background: Small molecule inhibitors of phosphatidylinositol-3 kinase (PI3K) have been developed as molecular therapy for cancer, but their efficacy in the clinic is modest, hampered by resistance mechanisms. Methods: We studied the effect of PI3K therapy in patient-derived tumor organotypic cultures (from five patient samples), three glioblastoma (GBM) tumor cell lines, and an intracranial model of glioblastoma in immunocompromised mice (n = 4-5 mice per group). Mechanisms of therapy-induced tumor reprogramming were investigated in a global metabolomics screening, analysis of mitochondrial bioenergetics and cell death, and modulation of protein phosphorylation. A high-throughput drug screening was used to identify novel preclinical combination therapies with PI3K inhibitors, and combination synergy experiments were performed. All statistical methods were two-sided. Results: PI3K therapy induces global metabolic reprogramming in tumors and promotes the recruitment of an active pool of the Ser/Thr kinase, Akt2 to mitochondria. In turn, mitochondrial Akt2 phosphorylates Ser31 in cyclophilin D (CypD), a regulator of organelle functions. Akt2-phosphorylated CypD supports mitochondrial bioenergetics and opposes tumor cell death, conferring resistance to PI3K therapy. The combination of a small-molecule antagonist of CypD protein folding currently in preclinical development, Gamitrinib, plus PI3K inhibitors (PI3Ki) reverses this adaptive response, produces synergistic anticancer activity by inducing mitochondrial apoptosis, and extends animal survival in a GBM model (vehicle: median survival = 28.5 days; Gamitrinib+PI3Ki: median survival = 40 days, P =.003), compared with single-agent treatment (PI3Ki: median survival = 32 days, P =.02; Gamitrinib: median survival = 35 days, P =.008 by two-sided unpaired t test). Conclusions: Small-molecule PI3K antagonists promote drug resistance by repurposing mitochondrial functions in bioenergetics and cell survival. Novel combination therapies that target mitochondrial adaptation can dramatically improve on the efficacy of PI3K therapy in the clinic. © 2015 The Author. Source
Tavecchio M.,Prostate Cancer Discovery and Development Program |
Lisanti S.,Prostate Cancer Discovery and Development Program |
Lam A.,Prostate Cancer Discovery and Development Program |
Ghosh J.C.,Prostate Cancer Discovery and Development Program |
And 14 more authors.
Journal of Biological Chemistry | Year: 2013
Background: Signals originated from mitochondria can affect other intracellular compartments. Results: Decreased levels in mitochondrial cyclophilin D promote cell proliferation and cell motility via chemokine/STAT3 signaling. Conclusion: Mitochondria regulate nuclear gene expression. Significance: Interorganelle signaling affects cell proliferation and cell motility. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Source